Journal Article

Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study

Van Cutsem, Eric, Phillips, Gail D Lewis, Ajani, Jaffer A, Harle-Yge, Marie-Laurence, Thuss-Patience, Peter C, Shitara, Kohei, Shah, Manish A, Chung, Hyun Cheol, Althaus, Betsy L, Mansoor, Wasat, Bodoky, Gyorgy, van der Horst, Tina, Kang, Yoon-Koo, Ohtsu, Atsushi, Castro, Hugo

2017

Overview

Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939. Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1–23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2–18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7–9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1–11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87–1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group. Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. F Hoffmann-La Roche.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adenocarcinoma / Adenocarcinoma - chemistry / Adenocarcinoma - drug therapy / Adenocarcinoma - secondary / Adult / Aged / Aged, 80 and over / Anemia / Anemia - chemically induced / Antibodies, Monoclonal, Humanized - adverse effects / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Agents - adverse effects / Antineoplastic Agents - therapeutic use / Breast cancer / Bridged-Ring Compounds - adverse effects / Bridged-Ring Compounds - therapeutic use / Cancer therapies / Chemotherapy / ErbB-2 protein / Esophagogastric Junction / Esophagus / Febrile Neutropenia - chemically induced / Female / Follow-Up Studies / Gastrectomy / Gastric cancer / Gastrointestinal Hemorrhage - chemically induced / Gene amplification / Growth factors / Hematology, Oncology and Palliative Medicine / Hemorrhage / Humans / Immunotherapy / Intention to Treat Analysis / Intravenous administration / Male / Maytansine - adverse effects / Maytansine - analogs & derivatives / Maytansine - therapeutic use / Metastases / Metastasis / Middle Aged / Monoclonal antibodies / Motivation / Neutropenia / Oncology / Paclitaxel / Pneumonia / Pneumonia - chemically induced / Population studies / Receptor, ErbB-2 - analysis / Retreatment / Stomach Neoplasms - chemistry / Stomach Neoplasms - drug therapy / Stomach Neoplasms - pathology / Survival / Survival Rate / Targeted cancer therapy / Taxoids - adverse effects / Taxoids - therapeutic use / Thrombocytopenia / Thrombocytopenia - chemically induced / Trastuzumab